Process for the preparation of dihydrometoxazinone derivatives and products so obtained

ABSTRACT

Dihydrometoxazinone derivatives with an antihypertensive action are prepared by condensing a cyano ester of general formula:   IN WHICH R6 is a substituted or unsubstituted phenyl group with an aldehyde or a ketone, the condensation being carried out in an acid medium in the presence of acetic anhydride. The resulting derivatives may then be reduced or the lactime form thereof may be acetylated.

United States Patent [1 1 Cordier et al.

[22] Filed: Aug. 23, 1972 [21] Appl. No.: 282,903

[52] U.S. Cl 26 0/244 R, 260/340.9, 260/465 D,

424/248 [51] Int. Cl C07d 87/08 [58] Field of Search 260/244 [56]References Cited UNITED STATES PATENTS 3,723,442 3/1973 Nakanishi et al.260/244 Primary ExaminerI-larry I. Moatz Attorney, Agent, or Firm-Youngand Thompson Feb. 11, 1975 [57] ABSTRACT Dihydrometoxazinone derivativeswith an antihypertensive action are prepared by condensing a cyano esterof general formula:

(C; R C\H C COOC H in which R is a substituted or unsubstituted phenylgroup with an aldehyde or a ketone, the condensation being carried outin an acid medium in the presence of acetic anhydride. The resultingderivatives may then be reduced or the lactime form thereof may beacetylated.

7 Claims, N0 Drawings COOC H COONH A PROCESS FOR THE PREPARATION OFDII-IYDROMETOXAZINONE DERIVATIVES AND PRODUCTS SO OBTAINED BACKGROUND OFTHE INVENTION 1. Field of the Invention This invention relates toprocesses for the production of dihydrometoxazinone derivatives havingan antihy- 'pertensive action, andto the derivatives so produced.

SUMMARY According to the inventiona process for producing derivatives ofdihydrometoxazinones of the general formula:

: l L c H ooc \/\K' in which R is selected from the group consisting ofH, CH OCH SCH and OH; R is selected from the group consisting of H, CHOCH SCH Cl, F and OH; R; is selected from the group consisting of H, OCHSCH and OH; or R and R together form the group -O-CH -O-; R is selectedfrom the'group consisting of H. Cl, OH, OCH and SCH R is selected fromthe group consisting of H. Cl, OH, OCH and SCH Ra 'is selected from thegroup consisting of COOCH -COOK, COONa. -CONHNH COOC H and -COOC H R isselected from the group consisting of H, CH CH CI, C H C H and C H R isselected from the group consisting of CH C H C H C H (OCH;,),,, C H(Cl),, and C H (SCH and is' selected from the group consisting of C H(2)ClC H and CH -C H comprises condensing a carbonyl compound with acyano ester in an acid medium,

i.e., ata pH lower than 7 in the presence of acetic anhydride,

At least one of the substituents R R R R, and R may be selected to bedifferent from H.

In practice the cyano ester generally is a derivative of ethylalpha-cyanophenylpyruvate of the general for-. mula:

R CH c com n in which the substituent R may be the radical andpreferably is selected from the group consisting of s 5 P( C6H4; P( 3) 64i P( 3) C6H4; P(CH3) C6H4; P(F)C6H4; 3) P( a) s ai P( 3) (OCHZOCGHS; P(a) a) s zil P( 6 4;

0\ t CH C p( 6 3; a)P( a) a) C H m(SCH )p(SCH C H and m(OH)p(OH)- m(OH)CH and the carbonyl compound is an aldehyde or a ketone, e.g., of generalformula R-C-Q'.

Advantageously the aldehyde is selected from the group consisting ofbenzoic aldehyde, 4- chlorobenzaldehyde, and paramethoxybenzoicaldehyde,'whilst the ketone is advantageously selected from the groupconsisting of cyclohexanone, acetone, monochloracetone, methylethylketone and 2- chlorocyclohexanone, and any substituted cyclanone.

According to an embodiment of the invention the acid medium is anaceto-sulphuric reaction medium.

Suitably in order to prepare the tetrahydro 2-3, 5-6 derivatives offormula (I) and/or (")the dihydro 2, 3 derivative of formula (I) isfirst prepared and is then chemically reduced.

Generally, in an acid reaction medium of definite composition, acyano-ester such as a derivative of ethyl alpha-cyano-phenylpyruvate iscondensed with a carbonyl compound such as an aldehyde or ketone.

The derivative of ethyl alpha-cyano-phenylpyruvate used as the startingreagent is advantageously selected from the following compounds:

CN H:

All) CN Taking the first compound of this series namely ethylalpha-cyanophenylpyruvates, as an example, the condensation reactionwith an aldehyde or a ketone can be written as follows:

As the reaction diagram shows, the cyano-ester intervenes because of itsenolic structure and causes the variation of the substituents R and R ofthe aldehyde or the ketone and it is thus possible to obtain an entireseries of derivatives of dihydro-2,3-metoxazinones of the formula (I).The above reaction thus takes place in two phases:

the first phase A: because of the acidity of the reaction medium, thecyano-ester is converted into the corresponding amide.

the second phase B; condensation of the amideenol with the hydrated formof the aldehyde or the ketone and the formation of the desiredheterocycle oxazinel 3-one-4.

The carbonyl compound may be a compound selected from the following:

; c14 co 9a CH co ca Cl; ca -co-c H;

The various possible combination of substituents R R R R R of thecyano-ester and R, R' of the carbonyl compound thus makes it possible bya single chemical reaction to synthesise an entire family of dihydro-2-3compounds of the formula (I).

The cyano-ester may be first prepared by, for example, condensing asubstituted phenylacetic nitrile with ethyl oxalate in the presence ofsodium ethylate;

The phase A of the synthesis process may be carried out by preparing afirst mixture containing:

the selected c'yano-ester;

acetic acid;

acetic anhydride; and

the selected carbonyl compound.

This mixture, which may be prepared at ambient temperature, isadvantageously cooled to temperature which varies according to thechoice of the reaction products. but which is generally between 5 and20C and frequently of the order of l0 or 15C. This cooling may becarried out, for example, by means of a thermostatic bath of cold water.A second mixture in iced water of:

concentrated sulphuric acid; and

acetic acid may then be added dropwise to the first cooled mixture, carebeing taken to ensure that the temperature of the reaction medium doesnot exceed about 20C. The agitation is suitably continued for 45 to 90minutes at a temperature between and 22C. It is worth noting thatexperimental studies have shown that these conditions of duration ofagitation and temperature are important for the yield of the reaction.

' Furthermore, it has been proved that the yield was considerablyimproved by the presence of acetic anhydride in the reaction medium.

The dihydro-2,3-metoxazinone of the formula (I) can then be extractedfrom its reaction medium and purified by recrystallisation.

The corresponding derivatives with saturated heterocyclic ring, that isto say the tetrahydro-2-3, 5-6 metoxazinones of the formula (I) can beobtained from dihydro-2-3 derivatives prepared by the hydrogenation ofthe ethylenic bond at 5 and 6 positions. The ethylenic oxazinones can bereduced by means of sodium amalgam containing 12 percent of sodiummetal, in an acetic acid medium, whilst maintaining a temperature of theorder of 15 to C so as to ensure a high yield from the reaction.

(:1 c i o The reduced oxazinone can be extracted by means of a suitablesolvent and recrystallised, giving either fine white needles ormonocrystals, or an amorphous powder corresponding to a mixture of thecis and trans isomers.

DESCRlPTlON OF THE PREFERRED EMBODIMENTS Preparation of ethylenicoxazinones of the formula (I) EXAMPLE I The preparation of:

A 600-ml beaker containing 22 g of ethyl alphacyanopyruvate, 9O mls ofanalytically pure anhydrous acetic acid, 30 mls of analytically pureacetic anhydride and 12 mls of cyclohexanone was placed on a magneticagitator.

The mixture was cooled by means of a thermostatic bath of cold water at10C and then subjected to agitation whilst a mixture containing 15 mlsof concentrated sulphuric acid and 30 mls of acetic acid, cooled in icedwater was added dropwise thereto. This addition caused the reactionmedium to heat up, but the temperature rise was controlled so that thereaction temperature did not exceed 20C. The agitation was continued for45 minutes at about 15C and then 15 minutes at ambient temperature. Anextraction was then carried out with ether, adding 200 mls of diethylether. The resulting etherified solution was poured into a separatingfunnel and then 400 mlsof water were added; after agitation the etherphase was collected; the residual aqueous phase was extracted threetimes using I00 mls of diethyl ether each time. The ether phases werecombined in the separating funnel and neutralised by the.

tion product was observed at the ether/water interface.

The product was filtered using a Buchner funnel and washed withdistilled water. The product. pale yellow due to the presence ofimpurities, was dissolved in ethanol at 95C on ahot water bath, and thesolution was then cooled, and a quantity of eold'distilled watersufficient to recrystallise the product was added whilst agitating thecooled solution. After allowing the resulting mixture to stand for 6hours, the recrystallised product was collected on a Buchner funnel. Bywashing with distilled water and drying to constant weight in an oven at80C 20.5 g of fine white needles with a melting point of 150C (yield:approximately 64.2 percent), were obtained.

EXAMPLE II The preparation of:

CZHSOOC O 12 g of paramethoxylated ethyl alphacyanophenylpyruvate, 45mls of anhydrous acetic acid. 15 mls of acetic anhydride and 6 mls ofcyclohexanone were introduced into a beaker and heated as described inExample 1. A mixture containing mls of concentrated sulphuric acid andmls of acetic acid was then added dropwise to the resulting mixture. Theprocedure of Example 1 was followed; the period of agitation being 1hour at 10C and 10 minutes at ambient temperature.

The product was extracted and purified as described in Example I and13.5 g of fine white needles with a melting point of 160C (yield: 80.5percent) were obtained.

EXAMPLE III The preparation of:

021150 on o EXAMPLE IV The preparation of:

- l onnooo o 6.3 g of the following compound, prepared as described inExample 1 CsHsOOC 0 were dissolved in the cold or on a lukewarm waterbath in 200 mls of anhydrous acetic acid. The vessel containing theacetic acid solution was placed in a cold thermostatic bath on amagnetic agitator and the temperature was maintained at between 10C and20C (10C being the temperature at which the reduction commences). 500 gof 12 percent sodium amalgam was added in small portions whilst thereaction mixture was maintained under violent agitation so as to ensurea vigorous contact between the amalgam and the dissolved product. Eachportion of amalgam was added only after the end of the evolution ofmolecular hydrogen. As the reaction is exothermic care was taken toensure that the temperature of the reaction medium did not exceed 20C.In this procedure, when the solution thickens, 50 mls of acetic acid maybe added.

After reduction, the reaction mixture and the mercury were poured into aseparating funnel. The mercury was recovered, and washed with a fewmillilires of acetic acid, which were then added to the main acetic acidsolution. The resulting acetic acid solution was neutralised with 1/10potassium bicarbonate and a milky mixture, with the oily reduced productfloating on top was obtained. The acidity was completely neutralised bymeans of powder potassium bicarbonate and the reduction produce wassalted out.

The extraction was carried out by treating the solution with chloroformand the chloroform was distilled off under a partial vacuum. After thetotal evporation of the solvent, the reduction product remained at thebottom of the flask in the form of a colourless or pale yellow oil whichmay sometimes crystallise spontaneously. The oil was dissolved in hotethanol at 95C and then recrystallised by cooling and wetting thealcoholic solution with water.

The product'was recovered on a Buchner funnel, washed and then dried atC. 50.9 grams of fine white needles, the melting point of which is 141C(yield: approximately 94 percent) were obtained.

EXAMPLE v The preparation of:

6.5 g of the compound prepared as described in Example (II) above, weredissolved in the cold or on a hot water bath in 200 mls of acetic acid,and were reduced with 500 g of 12 percent sodium amalgam underconditions identical to those of the general method of the Example lV.

After recrystallisation in ethanol and water and after allowing thesolution to stand for 24 hours 5.5 g of product whose melting point is162C (yield: approximately 85 percent) was obtained.

In all these one obtains the mixture of two of the cis and transisomeric forms. The separation of the two forms may be carried out byfractional crystallisation.

The preparation of derivatives of the formula '(I) in which Ra COOC Hcan be carried out as follows: the ethyl ester function of the carbon inposition 6 on the oxazinone ring of general formula (I) may be convertedby controlled saponification into a carboxylic acid. Starting off fromsuch an acid, the corresponding water-soluble alkali salts of sodium,potassium, ammo nium can be prepared. It should be observed that thepotassium salt may be of additional therapeutical interest for themolecule because of the fact that it supplies the K ion. The acidfunction may also be converted into the methyl ester by the action ofthe diazomethane 0n the acid. This conversion may be interesting fromthe pharmacological point of view. By this method the correspondingderivatives of the formula (I) in which Ra COOC H can be obtained with ayield higher than 99 percent. By reacting hydrazine hydrate on the ethylester function one obtains the corresponding hydrazide of the formula(I); this conversion is important because it makes it possible on theone hand to obtain watersoluble saturated derivatives of the formula(I), and on the other hand to obtain a pharmacological synergism byintroducing the hydrazide group.

The compound:

O H500C Lactim TNH 021150 0 C- O/ Lactam )o0oH3 controlled a acetylationl 0211 00c 5 Thus compounds of the formula (ll) are obtained.

The acetylation, extraction, and purification are generally carried outwith a yield of 80 percent. Moreover, this conversion could haveimportant consequences on a pharmacological level, since very often theacetylation of a drug makes it more active.

From tests which have been carried out it has been found that thesubstituents R and R of the derivatives of formulae (1) and (II) seem tobe of interest for the purpose of carrying the active molecule to itsreceptor in the body; whereas the substituents R R R R and R areinteresting from the point of view of the activity of the product. Therespective activities of the com pounds:

onto- 011 NlI I If E A onnooc 0 (A) ll 0 NH l l ozrrsooo o (B) l l/CzlLaOOC 0 prepared in accordance with the above Examples have beenclassified in the order ofsequence (a) (b) (c); the products (a) beingmuch more active than the others.

It has been found that the appearance of the antihypertensive action ofthe metaxozinone derivatives of general formulae (I) and (II) depends ontwo factors; the hydrogenation of the heterocycle; and the substitutionof the benzene ring.

Comparing the structures of the catecholamines:

OH R

R H: Noradrenaline R CH Adrenaline which are the active principles ofthe adrenal capsules which cause hypertension, with those of theoxazinones with a good antihypertensive activity:

C @OH \NH and l l CH C \m 0 021E000 0 g one can see a certain analogy inconformation. The substituents R and R provided they are notmetabolisable, could contribute to hooking the molecule Furthermore, thederivatives of the series of the dihydro-2,3-metaxazinones may serve asreference reagents for the standardisation of titration solutions of theN/lO alkali metal methylate solution type, as is shown by the examplegiven below:

An accurately weighed sample P of between 0.100 g and 0.200 g ofethyl-6-oxo-4-dihydro-2,3-metoxazinespirocyclohexyl-Z-phenyl-5-carboxylate was placed in a ml conical flask.

The sample was then dissolved in a solvent of the following composition:

dimethylforrnamide, analytical reagent 200 mls piperidine analyticalreagent 50 mls Two drops of a 0.5 percent solution of phenolphtha- Ienewere added to the dimethylformamide.

The flask was then placed on a mechanical agitator and air N/lO sodiummethylate solution was added by means of a burette graduated in 1/100ml. The end point is reached when the solution turns from light yellowto orange-red yellow, and this colouration must remain stable for atleast 30 seconds.

If N is the required content of the sodium methylate solution, n is thenumber of mls of sodium methylate solution run in during a blank testwithout the dihydro- 2,3-metoxazine derivative, n is the number of mlsof sodium methylate solution run in during the determination, the exactcontent of the sodium methylate solution is:

It should be observed that all the derivatives of the series ofdihydro-2,3-metoxazines can serve in this way as a reference substancefor the titration of solutions of sodium methylate, potassium methylateand lithium methylate.

Under the experimental conditions described, all the derivatives of theabove series behave as mono-acids and are very stable in the dry state.

We claim:

1. A process for the preparation of a derivative of 2,-3,5,6-tetrahydrometoxazinone with a hypertensive action of the formulain which R is selected from the group consisting of H, CH OCl-l SCH andOH; R is selected from the group consisting of H, CH OCH SCH Cl, F andOH; R, is selected from the group consisting of H, OCH SCH and OH; R, isselected from the group consisting of H, Cl, OH, OCH and SCH R isselected from the group consisting of H, Cl, OH, OCH and SCI-l Ra isselected from the group consisting of COOCH COOC H COOC H COOC H COONa,COOK, COONH and CONH-NH R and R are se lected together from the groupconsisting of C ll C H CI, C H

said process comprising forming a mixture of a cyanester of the formulaand a carbonyl compound of formula and acetic anhydride and acetic acidat a temperature between and 20C. thereby to form the amidecorresponding to said cyanester, adding acetic acid and concentratedsulfuric acid to the reaction medium containing said amide at atemperature between and 22C. to make a 2,3-dihydrometoxazinonederivative, extracting said dihydrometoxazinone, and reducing saiddihydrometoxazinone derivative in an acetic acid medium by means ofsodium amalgam containing 12 percent of sodium metal while maintaining atemperature of the order of 15 to C. to obtain the corresponding2,3,5,-tetrahydrometoxazinone.

2. A process as claimed in claim 1, wherein at least one of thesubstituents R R R R and R is selected to be different from H.

3. A process as claimed in claim 1, in which the cyanoester is aderivative of ethyl alphacyanophenylpyruvate of the following formula:

0 l CIH c cooc n group consisting of benzaldehyde, 4-chlorobenzaldehyde, and paramethoxy-benzaldehyde.

5. A process as claimed in claim 3, in which the carbonyl compound is aketone selected from the group consisting of cyclohexanone, acetone,monochloracetone, methylethyl ketone and 2-chlorocyclohexanone.

6. A derivative of 2,3,5,6-tetrahydrometoxazinone of the formula:

1 5 1% R2 (In M /R MK in which R, is selected from the group consistingof H, CH OCH SCH and OH; R is selected from the group consisting of H,CH OCH SCH Cl, F and OH; R, is selected from the group consisting of H,OCH SCH and OH; R, is selected from the group consisting of H, Cl, OH,OCH, and SCH- R is selected from the group consisting of H, Cl, OH, OCHand SCH Ra is selected from the group consisting of COOCH COOC H COOC HCOOC H COONa, COOK, COONH CONH-NH R and R are selected together from thegroup consisting of 7. A derivative of tetrahydrometoxazinone of theformula

1. A process for the preparation of a derivative of2,3,5,6-tetrahydrometoxazinone with a hypertensive action of the formula2. A process as claimed in claim 1, wherein at least one of thesubsTituents R1, R2, R3, R4 and R5 is selected to be different from H.3. A process as claimed in claim 1, in which the cyanoester is aderivative of ethyl alpha-cyanophenylpyruvate of the following formula:4. A process as claimed in claim 3, in which the carbonyl compound is analdehyde selected from the group consisting of benzaldehyde,4-chlorobenzaldehyde, and paramethoxy-benzaldehyde.
 5. A process asclaimed in claim 3, in which the carbonyl compound is a ketone selectedfrom the group consisting of cyclohexanone, acetone, monochloracetone,methylethyl ketone and 2-chlorocyclohexanone.
 6. A DERIVATIVE OF2,3,5,6-TETRAHYDROMETOXAZINONE OF THE FORMULA:
 7. A derivative oftetrahydrometoxazinone of the formula